Abstract

RESEARCH DESIGN AND METHODS Data were pooled from the Atherosclerosis Risk in Communities, Cardiovascular Health, and Framingham Offspring studies (n = 20,581). Incident coronary heart disease and stroke events were ascertained over 9 years.

RESULTS The sensitivity for incident CVD events was higher and the specificity lower for the empirically derived versus the Adult
Treatment Panel (ATP) III, International Diabetes Federation (IDF), or Harmonized metabolic syndrome definitions (sensitivity/specificity
0.65/0.53 vs. 0.53/0.63, 0.51/0.66, and 0.64/0.56, respectively), resulting in no overall improvement in discrimination. Multivariable-adjusted
hazard ratios for incident CVD events were similar across definitions and were 1.7 (95% CI 1.6–1.9) for ATP III, 1.8 (1.6–2.0)
for IDF, 1.9 (1.7–2.0) for Harmonized, and 1.7 (1.6–1.9) for the empirically derived definition.

CONCLUSIONS Empirical derivation of the metabolic syndrome definition did not improve CVD discrimination or risk prediction.

A number of different definitions for the metabolic syndrome have been proposed (1–4), with the cut points for each component and their combinations derived primarily from expert opinion. The lack of an empirically
derived definition hinders evaluation of opposing arguments concerning the clinical utility of the metabolic syndrome.

RESEARCH DESIGN AND METHODS

Data from the prospective Framingham Offspring, Atherosclerosis Risk in Communities (ARIC), and Cardiovascular Health studies
were pooled as previously described (5). Informed consent and appropriate institutional review board approval were obtained for each study. For the Framingham Offspring
Study, the fourth examination was used as the baseline visit because it was the first time point at which waist circumference
was measured. Individuals reporting a history of cardiovascular disease (CVD) at baseline, fasting <8 h, aged <45 years, or
underweight (BMI <18.5 kg/m2) were excluded.

CVD outcomes included probable and definite fatal and nonfatal coronary heart disease (CHD) and stroke for all studies (6–9). CHD was defined as myocardial infarction, silent myocardial infarction, or CHD death, and stroke included both hemorrhagic
and ischemic subtypes.

Participants were classified as having metabolic syndrome according to three existing definitions as follows. ATP III definition,
three or more of the following criteria: 1) waist circumference >102 cm in men and >88 cm in women, 2) triglycerides ≥1.7 mmol/L, 3) HDL cholesterol <1.0 mmol/L (men) or <1.3 mmol/L (women), 4) blood pressure ≥130/85 mmHg or antihypertensive medication use, and 5) glucose ≥5.6 mmol/L or antidiabetes medication use (or physician diagnosis for ARIC). International Diabetes Federation
(IDF) definition, abdominal adiposity (waist circumference ≥94 cm [men] or ≥80 cm [women]) and two or more risk factors from
numbers 2 through 5 above. Harmonized definition, identical to the ATP III definition except that IDF waist circumference
cut points were used. Information on medications for raising HDL cholesterol, needed for the Harmonized definition, were not
ascertained but were expected to be infrequent given that baseline exams occurred prior to 1992.

The cut point for each component of the metabolic syndrome and the resulting number of such cut points that maximized the
sum of sensitivity and specificity for incident CVD events were calculated. The relative integrated discrimination improvement
(RIDI) was then calculated (10), with values greater than zero indicating better overall discrimination for empirically derived versus existing definitions.
Cox proportional hazards regression was used to calculate hazard ratios (HRs) for incident CVD events associated with each
metabolic syndrome definition, adjusting for age, sex, race, education level, smoking status, alcohol intake, and study (ARIC,
Cardiovascular Health Study [CHS], and Framingham Offspring).

RESULTS

Across the three studies (n = 20,581), 1,783 incident CVD events occurred over 9 years of follow-up. In the overall sample, the optimal systolic and
diastolic blood pressure and triglyceride cut points were lower than those in existing definitions, whereas the glucose cut
point was identical (Table 1). Within demographic subgroups, the optimal cut point varied by component and subgroup.

The presence of ≥3 components at levels above the optimal cut point (below the optimal cutpoint for HDL cholesterol), identified
in Table 1, provided the highest sum of sensitivity and specificity, and two empirically derived metabolic syndrome definitions were
created: 1) three or more components using cut points derived in the full sample (uniform cut point definition) and 2) three or more components using demographic subgroup-specific cut points.

All metabolic syndrome definitions were associated with an increased HR for incident CVD in multivariable-adjusted analyses
(1.7 [95% CI 1.6–1.9], 1.8 [1.6–2.0], and 1.9 [1.7–2.0] for ATP III, IDF, and Harmonized, respectively, and 1.7 [1.6–1.9]
and 1.8 [1.6–1.9] for the empirically derived uniform and subgroup-specific cut point definitions, respectively). Results
were similar among individuals without hypertension or diabetes or when the HRs were adjusted for antihypertensive and lipid-lowering
medication use. A fivefold cross-validation study resulted in identical cut points and similar performance characteristics.

CONCLUSIONS

The data-derived definitions of the metabolic syndrome resulting from maximization of the sum of sensitivity and specificity
for CVD events resulted in little improvement in discrimination compared with existing definitions. Also, the HRs for CVD
associated with each metabolic syndrome definition were similar.

The empirical derivation resulted in cut points similar to those based on expert opinion used in existing metabolic syndrome
definitions. The exception was the empirically derived triglyceride cut point (1.4 mmol/L), which was substantially lower
than that used in existing definitions (1.7 mmol/L). The lower triglyceride cut point resulted in a higher prevalence of the
metabolic syndrome but no overall improvement in discrimination or meaningful difference in the HR for CVD.

For the ATP III, IDF, and Harmonized definitions, sex-specific cut points are applied for HDL cholesterol and waist circumference
criteria. In the current study, subgroup-specific cut points resulted in higher sensitivity in some groups at the expense
of lower specificity. In other subgroups, specificity was higher but sensitivity lower. Given this, the lack of improvement
in discrimination when using subgroup-specific cut points, and the similarity of HRs between the empirically derived uniform
cut point definition and existing definitions, which use sex-specific cut points, these data suggest that uniform cut points
in all subgroups may be sufficient for discrimination and assessing associations. This results in a simplified clinical application.

Although measurement protocols were not identical across the three studies, findings were similar within each study (data
not shown). The strength of this study comes from the use of a large sample with over 1,700 incident CVD events.

Although the ATP III, IDF, and Harmonized definition cut points were not empirically derived, the improvements in CVD risk
prediction seen with empirically derived cut points were small, suggesting that the existing metabolic syndrome definitions
will be sufficient for use in clinical practice and research studies should the metabolic syndrome debate conclude in a recommendation
for its continued use.

Acknowledgments

This study was supported by a grant from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes
of Health (R21 HL089625 [to R.P.W.]). The CHS, ARIC, and Framingham Offspring Study are conducted and supported by the NHLBI
in collaboration with the CHS, ARIC, and Framingham Offspring Study investigators, respectively.

No potential conflicts of interest relevant to this article were reported.

R.P.W. was involved in the design of the study and wrote the manuscript. A.P.M. designed data analysis programs, wrote the
statistical methods section, and edited the manuscript. M.K. was involved in the design of the study and edited the manuscript.
P.M. was involved in the design of the study, assisted with data analysis, and edited the manuscript. D.W. performed the statistical
analysis. H.W.C. was involved in the design of the study and edited the manuscript. A.D.O. edited the manuscript. K.R. was
involved in the design of the study and edited the manuscript. V.F. was involved in the design of the study and edited the
manuscript.

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